Difluoromethylation of Heterocycles with Tetrafluoroethylene

Abstract

A purpose of the present invention is to provide a simple and low cost method that enables production of a difluoromethyl-substituted aromatic heterocyclic compound at a high yield. Another purpose of the present invention is to provide a simple and low cost method that enables production of an aromatic heterocyclic ring-substituted difluoroacetic acid derivative at a high yield.　The present invention pertains to a method that is for producing a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by formula (IIa) and that is characterized by causing, in the presence of a base, an N-oxide aromatic heterocyclic compound having a partial structure represented by formula (Ia) to react with tetrafluoroethylene in a solvent selected from aromatic hydrocarbon solvents, ester solvents, and ether solvents. [Symbols in the formulae are as described in the description.]　The present invention pertains to a method that is for producing an aromatic heterocyclic ring-substituted difluoroacetic acid derivative having a partial structure represented by formula (IIIb) and that is characterized by causing, in the presence of a base and a compound represented by formula (IIb): R-YH, an N-oxide aromatic heterocyclic compound having a partial structure represented by formula (Ib) to react with tetrafluoroethylene in a solvent selected from aromatic hydrocarbon solvents, ester solvents, and ether solvents. [Symbols in the formulae are as described in the description.]

Description

[Technical Field]

[0001] The present invention relates to a method for producing a difluoromethyl-substituted aromatic heterocyclic compound, and a method for producing a difluoroacetic acid derivative substituted with an aromatic heterocycle. [Background technology]

[0002] Fluorine-containing alkyl group-substituted aromatic heterocyclic compounds, particularly difluoromethyl-substituted aromatic heterocyclic compounds, are useful as synthetic intermediates for pharmaceuticals or agricultural chemicals.

[0003] The method for producing a fluorine-containing alkyl group-substituted aromatic heterocyclic compound includes the following steps: A method for producing 2-(1,2,2,2-tetrafluoroethyl)quinoline by reacting quinoline N-oxide with hexafluoropropene (CF2=CFCF3) at room temperature in N,N-dimethylformamide and water in one or two steps (Non-Patent Document 1, Scheme 5); A method for producing 2-(1,2,2,2-tetrafluoroethyl)quinoline by reacting quinoline N-oxide with hexafluoropropene (CF2=CFCF3) in N,N-dimethylformamide at room temperature (Non-Patent Document 2, Scheme 1 and Table 1); is known.

[0004] None of the documents describe the preparation of difluoromethyl-substituted aromatic heterocyclic compounds or their reaction with tetrafluoroethylene (CF2=CF2).

[0005] Aromatic heterocycle-substituted difluoroacetic acid derivatives are useful for the preparation of pharmaceutical or agrochemical synthesis intermediates.

[0006] Examples of methods for producing aromatic heterocycle-substituted fluoroalkylcarboxylic acid derivatives include, for example, a method for producing methyl 2-(2-heteroaryl)perfluoropropionate in two steps by reacting various aromatic heterocycle N-oxides with hexafluoropropene (CF2=CFCF3) and methanol in N,N-dimethylformamide (Scheme 5, Table 2), a method for producing 2-(2-heteroaryl)perfluoropropionic acid amide in two steps by reacting various aromatic heterocycle N-oxides with hexafluoropropene (CF2=CFCF3) and an amine in N,N-dimethylformamide (Schemes 12 and 13), and a method for producing methyl 2-chloro-2-fluoro-2-(2-quinolyl)acetate by reacting quinoline N-oxide with chlorotrifluoroethylene (CF2=CFCl) and methanol in N,N-dimethylformamide at 100°C (Scheme 17).

[0007] None of the documents describe the preparation of aromatic heterocycle-substituted difluoroacetic acid derivatives or their reaction with tetrafluoroethylene (CF2=CF2). [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Chem. Eur. J. 2008, vol.14, pp2577-2589 [Non-patent document 2] Mendeleev Commun. 2006, pp 161-163 Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide a method for producing a difluoromethyl-substituted aromatic heterocyclic compound in a simple, inexpensive manner and in good yield. Another object of the present invention is to provide a method for producing an aromatic heterocycle-substituted difluoroacetic acid derivative in a simple, inexpensive manner and in good yield. [Means for solving the problem]

[0010] As a result of intensive investigations aimed at solving the above-mentioned problems, the present inventors have found that a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by the following formula (IIa) can be produced in one step, simply, inexpensively, with little by-products, and in good yield by reacting an N-oxide aromatic heterocyclic compound having a partial structure represented by the following formula (Ia) with tetrafluoroethylene in a specific solvent in the presence of a base, thereby completing the present invention.

[0011] That is, the present invention is as follows (Invention a): [1a] In a solvent selected from an aromatic hydrocarbon solvent, an ester solvent, and an ether solvent, in the presence of a base, a compound of formula (Ia):

[0012] [ka]

[0013] The present invention relates to a compound represented by the formula (IIa):

[0014] [ka]

[0015] The present invention relates to a method for producing a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by the following formula (hereinafter, also referred to as difluoromethyl-substituted aromatic heterocyclic compound (IIa)). [2a] The method according to the above [1a], wherein the reaction is carried out at a temperature within the range of 100 to 300°C. [3a] The method according to the above [1a] or [2a], wherein the reaction is carried out in the range of 0.1 to 10.0 MPa. [4a] The production method according to any one of the above [1a] to [3a], wherein the reaction is carried out in the presence of a buffer solution having a pH of 5.0 to 8.0. [5a] The N-oxide aromatic heterocyclic compound having the partial structure represented by formula (Ia) is represented by formula (IA) or (IB):

[0016] [ka]

[0017] [In the formula, X 1a is CR 1a or indicates N; X 1b is CR 1b or indicates N; X 1c is CR 1c or indicates N; X 1d is CR 1d or indicates N; R 1a , R 1b , R 1c and R 1d are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 1a and R 1b , R 1b and R 1c , or R1c and R 1d together form a halogen atom, a cyano group, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 may form arenes; X 2a is CR 2a , N, NR 2a , indicates S or O; X 2b is CR 2b or indicates N; X 2c is CR 2c , N, NR 2c , indicates S or O; R 2a , R 2b and R 2c are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 2a and R 2b , or R 2b and R 2ctogether form a halogen atom, a cyano group, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 may form an arene.] The method for producing an N-oxide aromatic heterocyclic compound represented by the formula (hereinafter also referred to as N-oxide aromatic heterocyclic compound (IA) or (IB)) is described in any one of the above [1a] to [4a].

[0018] [6a] The N-oxide aromatic heterocyclic compound having the partial structure represented by formula (Ia) is represented by formula (IA), and R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d together form a halogen atom, a cyano group, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 The method according to [5a] above, wherein an arene is formed.

[0019] [7a] The N-oxide aromatic heterocyclic compound having the partial structure represented by formula (Ia) is represented by formula (IA), and R 1a , R 1b , R 1c and R 1d are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 The method according to the above [5a], wherein the aryl group is an aralkyl group.

[0020] [8a] The N-oxide aromatic heterocyclic compound having the partial structure represented by formula (Ia) is represented by formula (IB), and R 2a and R 2b , or R 2b and R 2c together form a halogen atom, a cyano group, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 The method according to [5a] above, wherein an arene is formed.

[0021] [9a] The N-oxide aromatic heterocyclic compound having the partial structure represented by formula (Ia) is represented by formula (IB), and R 2a , R 2b and R 2c are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 The method according to the above [5a], wherein the aryl group is an aralkyl group.

[0022] Furthermore, as a result of intensive studies to solve the above-mentioned problems, the present inventors have found that an aromatic heterocycle-substituted difluoroacetic acid derivative having a partial structure represented by formula (IIIb) below can be produced in one step, simply, inexpensively, and with good yield and with few by-products, by reacting an N-oxide aromatic heterocyclic compound having a partial structure represented by formula (Ib) below with tetrafluoroethylene in a specific solvent in the presence of a compound represented by formula (IIb) below and a base, thereby completing the present invention.

[0023] That is, the present invention is as follows (Invention b): [1b] in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent, and an ether solvent, [In the formula, R is C 1-8 Alkyl group, C 3-8 Cycloalkyl groups, C 7-16 Aralkyl group or C 6-10 represents an aryl group, wherein the C 1-8The alkyl group may contain halogen atoms, cyano groups, C 1-6 Alkoxy groups and C 1-6 haloalkoxy groups, 3-8 Cycloalkyl groups, C 7-16 Aralkyl groups and C 6-10 The aryl group is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 haloalkoxy groups, Y is O, S or NR Y indicates, R Y is a hydrogen atom or C 1-8 It may represent an alkyl group, or may be taken together with R to form a nitrogen-containing heterocycle together with the nitrogen atom to which they are attached. In the presence of a compound represented by formula (Ib) (hereinafter also referred to as compound (IIb)) and a base,

[0024] [ka]

[0025] and reacting an N-oxide aromatic heterocyclic compound having a partial structure represented by the formula (IIIb):

[0026] [ka]

[0027] [Each symbol in the formula has the same meaning as defined above.] A method for producing an aromatic heterocycle-substituted difluoroacetic acid derivative having a partial structure represented by the following formula (hereinafter also referred to as aromatic heterocycle-substituted difluoroacetic acid derivative (IIIb)). [2b] The method according to the above [1b], wherein the reaction is carried out at a temperature within the range of 100 to 300°C. [3b] The method according to the above [1b] or [2b], wherein the reaction is carried out in the range of 0.1 to 10.0 MPa. [4b] The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (Ib) is represented by formula (IA) or (IB):

[0028] [ka]

[0029] [In the formula, X 1a is CR 1a or indicates N; X 1b is CR 1b or indicates N; X 1c is CR 1c or indicates N; X 1d is CR 1d or indicates N; R 1a , R 1b , R 1c and R 1d are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 1a and R 1b , R 1b and R 1c , or R 1c and R1d together form a halogen atom, a cyano group, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 may form arenes; X 2a is CR 2a , N, NR 2a , indicates S or O; X 2b is CR 2b or indicates N; X 2c is CR 2c , N, NR 2c , indicates S or O; R 2a , R 2b and R 2c are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 2a and R 2b , or R 2b and R 2c together form a halogen atom, a cyano group, and C 1-6Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 may form an arene.] The method for producing an N-oxide aromatic heterocyclic compound represented by the formula (hereinafter also referred to as N-oxide aromatic heterocyclic compound (IA) or (IB)) is described in any one of the above [1b] to [3b]. [5b] The N-oxide aromatic heterocyclic compound having the partial structure represented by formula (Ib) is represented by formula (IA), and R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d together form a halogen atom, a cyano group, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 The method according to [4b] above, wherein an arene is formed. [6b] The N-oxide aromatic heterocyclic compound having the partial structure represented by formula (Ib) is represented by formula (IA), and R1a , R 1b , R 1c and R 1d are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 The method according to the above [4b], wherein the aryl group is an aralkyl group. [7b] The N-oxide aromatic heterocyclic compound having the partial structure represented by formula (Ib) is represented by formula (IB), and R 2a and R 2b , or R 2b and R 2c together form a halogen atom, a cyano group, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 The method according to [4b] above, wherein an arene is formed. [8b] The N-oxide aromatic heterocyclic compound having the partial structure represented by formula (Ib) is represented by formula (IB), and R 2a , R 2b and R 2care independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 The method according to the above [4b], wherein the aryl group is an aralkyl group. [Effects of the Invention]

[0030] According to the present invention (Invention a), a difluoromethyl-substituted aromatic heterocyclic compound (IIa) can be produced in a single step with a small amount of by-products and in a good yield by a simple and inexpensive method in which tetrafluoroethylene is introduced into an N-oxide aromatic heterocyclic compound (Ia) in a specific solvent in the presence of a base.

[0031] Furthermore, according to the present invention (Invention b), an aromatic heterocycle-substituted difluoroacetic acid derivative (IIIb) can be produced in a single step with a small amount of by-products and in a good yield by a simple and inexpensive method in which tetrafluoroethylene is introduced into an N-oxide aromatic heterocyclic compound (Ib) in the presence of compound (IIb) and a base in a specific solvent. DETAILED DESCRIPTION OF THE INVENTION

[0032] The definitions of groups used in the present specification are explained in detail below. Unless otherwise specified, groups have the following definitions.

[0033] In this specification, compounds represented by formulas are referred to by adding the formula number to the word "compound." For example, a compound represented by formula (1) is referred to as "compound (1)." In this specification, a numerical range expressed by "to" or "-" means a numerical range in which the numbers before and after "to" or "-" are the lower or upper limit. In this specification, when the element symbol "C" is used to indicate a numerical range with numbers before and after "-" attached to the name of an arbitrary group, it indicates an arbitrary group having an integer number of carbon atoms, with the numbers before and after "-" being the lower or upper limit. For example, an alkyl group having 1 to 3 carbon atoms is referred to as "C 1-3 The term "alkyl group" may refer to -CH3, -C2H5, -C3H7, etc. The same applies to other groups.

[0034] In this specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0035] In this specification, "C 1-8 The term "alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms. 1-8 Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, and octyl. 1-4 Alkyl groups are preferred.

[0036] In this specification, "C 1-6 The term "alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. 1-4 Alkyl groups are preferred.

[0037] In this specification, "C 1-4 The term "alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms.1-4 "Alkyl group" includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0038] In this specification, "C 1-20 The term "alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms. 1-20 Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, stearyl (octadecyl), and icosyl.

[0039] In this specification, "C 2-20 The term "alkenyl group" refers to a linear or branched unsaturated hydrocarbon group having 2 to 20 carbon atoms and at least one double bond. 2-20 Examples of the "alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl, 1-octenyl, 1-decenyl, 1-octadecenyl, and 1-icosenyl.

[0040] In this specification, "C 2-20 The term "alkynyl group" refers to a linear or branched unsaturated hydrocarbon group having 2 to 20 carbon atoms and at least one triple bond. 2-20 Examples of the "alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, 1-octynyl, 1-decynyl, 1-octadecynyl, 1-icosynyl, and the like.

[0041] In this specification, "C 1-20 The term "alkylidene group" refers to a divalent saturated hydrocarbon group formed by removing two hydrogen atoms from the same carbon atom of a linear or branched saturated hydrocarbon having 1 to 20 carbon atoms. 1-20Examples of the "alkylidene group" include methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, octylidene, decylidene, octadecylidene, icosylidene, and the like.

[0042] In this specification, "C 2-20 The term "alkenylidene group" refers to a divalent unsaturated hydrocarbon group formed by removing two hydrogen atoms from the same carbon atom of a straight-chain or branched-chain unsaturated hydrocarbon having 2 to 20 carbon atoms and at least one double bond. 2-20 Examples of the "alkenylidene group" include ethenylidene, propenylidene, butenylidene, pentenylidene, hexenylidene, octenylidene, desenylidene, octadecenylidene, icosenylidene, and the like.

[0043] In this specification, "C 3-20 The term "alkynylidene group" refers to a divalent unsaturated hydrocarbon group formed by removing two hydrogen atoms from the same carbon atom of a straight-chain or branched-chain unsaturated hydrocarbon having 3 to 20 carbon atoms and at least one triple bond. 3-20 Examples of the "alkynylidene group" include propynylidene, butynylidene, pentynylidene, hexynylidene, octynylidene, decynylidene, octadecynylidene, and icosynylidene.

[0044] In this specification, "C 1-6 An "alkoxy group" is a group of the formula R 11 O-(where R 11 is C 1-6 represents an alkyl group. 1-6 Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, and hexyloxy. 1-4 Alkoxy groups are preferred.

[0045] In this specification, "C 1-6 Haloalkyl group means "C 1-6"C" means a group in which one or more hydrogen atoms in the "alkyl group" are substituted with halogen atoms. 1-6 Examples of the "haloalkyl group" include fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, trifluoromethyl, difluoromethyl, perfluoroethyl, perfluoropropyl, chloromethyl, 2-chloroethyl, bromomethyl, 2-bromoethyl, iodomethyl, and 2-iodoethyl, with trifluoromethyl being preferred.

[0046] In this specification, "C 1-6 Haloalkoxy group means "C 1-6 "C" means a group in which one or more hydrogen atoms in the "alkoxy group" are substituted with halogen atoms. 1-6 Examples of the "haloalkoxy group" include bromomethoxy, 2-bromoethoxy, 3-bromopropoxy, 4-bromobutoxy, iodomethoxy, 2-iodoethoxy, 3-iodopropoxy, 4-iodobutoxy, fluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, tribromomethoxy, trichloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroethoxy, perfluoropropoxy, perfluoroisopropoxy, 1,1,2,2-tetrafluoroethoxy, and 2-chloro-1,1,2-trifluoroethoxy.

[0047] In this specification, "C 1-6 An "alkylsulfanyl group" is a group of the formula R 11 S-(where R 11 is C 1-6 represents an alkyl group. 1-6 Examples of the "alkylsulfanyl group" include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, and hexylsulfanyl. 1-4 The sulfanyl group is preferred.

[0048] As used herein, "mono-C 1-6 An "alkylamino group" is a group of the formula R 11 NH-(where R 11 is C 1-6 represents an alkyl group.) 1-6 Examples of the alkylamino group include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, and hexylamino. 1-4 Alkylamino groups are preferred.

[0049] As used herein, "di-C 1-6 An "alkylamino group" is a group of the formula R 11 2N-(where two R 11 are each independently 1-6 represents an alkyl group.) 1-6 Examples of the "alkylamino group" include dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, disec-butylamino, ditert-butylamino, dipentylamino, and dihexylamino. 1-4 Alkylamino groups are preferred.

[0050] In this specification, "C 1-6 An "alkoxy-carbonyl group" is a group of the formula R 11 OC(=O)-(where R 11 is C 1-6 represents an alkyl group. 1-6 Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. 1-4 Alkoxy-carbonyl groups are preferred.

[0051] In this specification, "C3-8 The term "cycloalkyl group" means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. 3-8 The "cycloalkyl group" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0052] In this specification, "C 3-8 The term "cycloalkenyl group" means a cyclic unsaturated hydrocarbon group having 3 to 8 carbon atoms. 3-8 The "cycloalkenyl group" includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0053] In this specification, "C 3-8 The term "cycloalkylidene group" refers to a divalent saturated hydrocarbon group formed by removing two hydrogen atoms from the same carbon atom of a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. 3-8 The "cycloalkylidene group" includes cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene, and cyclooctylidene.

[0054] In this specification, "C 3-8 The term "cycloalkenylidene group" refers to a divalent unsaturated hydrocarbon group formed by removing two hydrogen atoms from the same carbon atom of a cyclic unsaturated hydrocarbon group having 3 to 8 carbon atoms. 3-8 Examples of the "cycloalkenylidene group" include cyclopropenylidene, cyclobutenylidene, cyclopentenylidene, cyclohexenylidene, cycloheptenylidene, and cyclooctenylidene.

[0055] In this specification, "C 6-10 The term "aryl group" means a hydrocarbon group having 6 to 10 carbon atoms and having aromaticity. 6-10 The "aryl group" includes phenyl, 1-naphthyl, and 2-naphthyl, with phenyl being preferred.

[0056] In this specification, "C 7-16An aralkyl group is a group consisting of C 6-10 "C" substituted with "aryl group" 1-6 "C" means "alkyl group." 7-16 Examples of the "aralkyl group" include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, (1-naphthyl)methyl, (2-naphthyl)methyl, and the like, with benzyl being preferred.

[0057] In this specification, "C 6-10 "Arene" means a hydrocarbon ring having 6 to 10 carbon atoms and having aromaticity. 6-10 The "arenes" include benzene and naphthalene, with benzene being preferred. As used herein, "optionally substituted C 6-10 The substituents of "arene" include halogen atoms, cyano groups, C 1-6 Alkyl group, hydroxy group, C 1-6 Alkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 Examples include aralkyl groups.

[0058] In this specification, the term "heterocyclic group" refers to a ring containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and may be aromatic or non-aromatic. Examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridonyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. Examples of the "non-aromatic heterocyclic group" include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrobenzo[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydro ... and 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0059] In this specification, the term "nitrogen-containing heterocycle" refers to a ring containing at least one nitrogen atom and optionally containing a heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Examples of the "nitrogen-containing heterocycle" include aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine. A 3- to 8-membered nitrogen-containing heterocycle is preferred, and a 5- or 6-membered nitrogen-containing heterocycle is more preferred.

[0060] In this specification, the term "monovalent organic group" refers to a monovalent group that essentially contains a carbon atom. 1-20 Alkyl group, C 2-20 Alkenyl group, C 2-20 Alkynyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkenyl group, C 6-10 Aryl group, C 7-16 Examples of the "monovalent organic group" include hydrocarbon groups such as aralkyl groups; heterocyclic groups such as aromatic heterocyclic groups and non-aromatic heterocyclic groups; and the like. 1-6 Alkyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6Groups having a substituent such as an alkylamino group are also included.

[0061] In the present specification, the term "divalent organic group" refers to a divalent group that essentially contains a carbon atom, and in which the same carbon atom has two bonds. 1-20 Alkylidene group, C 2-20 Alkenylidene group, C 3-20 Alkynylidene group, C 3-8 Cycloalkylidene group, C 3-8 The "divalent organic group" includes a C 1-6 Alkyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Groups having a substituent such as an alkylamino group are also included.

[0062] In the present specification, examples of the "nitrogen-containing bicyclo ring" include 1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane, and the like.

[0063] In this specification, the term "unsaturated nitrogen-containing heterocycle" refers to a ring containing at least one double bond and at least one nitrogen atom, and may further contain a heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Examples of the "unsaturated nitrogen-containing heterocycle" include pyridine, imidazole, quinoline, and octahydropyrimido[1,2-a]azepine.

[0064] In the present specification, examples of the "counter anion" include halide ions, hydroxide ions, and the like. In this specification, the term "alkali metal" includes lithium, potassium, sodium, cesium, and the like.

[0065] The production method of the present invention (invention a) will be described below. In the present invention, the difluoromethyl-substituted aromatic heterocyclic compound (IIa) is produced by reacting the N-oxide aromatic heterocyclic compound (Ia) with tetrafluoroethylene in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent, and an ether solvent in the presence of a base. The reaction mechanism, for example, when a proton source is present and is water, is as follows:

[0066] [ka]

[0067] Specific examples of the N-oxide aromatic heterocyclic compound (Ia) include the following N-oxide aromatic heterocyclic compounds (IA) and (IB).

[0068] [ka]

[0069] [In the formula, X 1a is CR 1a or indicates N; X 1b is CR 1b or indicates N; X 1c is CR 1c or indicates N; X 1d is CR 1d or indicates N; R 1a , R 1b , R 1c and R 1d are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d together form a halogen atom, a cyano group, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 may form arenes; X 2a is CR 2a , N, NR 2a , indicates S or O; X 2b is CR 2b or indicates N; X 2c is CR 2c , N, NR 2c , indicates S or O; R 2a , R 2b and R 2c are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 2a and R 2b , or R 2b and R 2c together form a halogen atom, a cyano group, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 may form an arene.] R 1a , R 1b , R 1c and R 1d are preferably each independently a hydrogen atom, a cyano group or C 1-6 alkyl group or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, C 1-6 C optionally substituted with an alkoxy-carbonyl group 6-10 An arene may be formed. R 2a , R 2b and R 2c are preferably each independently a hydrogen atom, C 1-6 Alkyl group or C 7-16 an aralkyl group, or R 2a and R 2b , or R 2b and R 2cTogether, C 6-10 An arene may be formed.

[0070] In formula (IB), the bond R 2a -R 2b and bond R 2b -R 2c One of the bonds is a single bond and the other is a double bond. 2a When is S or O, bond R 2a -R 2b is a single bond, and bond R 2b -R 2c is a double bond. 2c When is S or O, bond R 2a -R 2b is a double bond, and bond R 2b -R 2c is a single bond.

[0071] Specific examples of the N-oxide aromatic heterocyclic compound (IA) include the following N-oxide aromatic heterocyclic compounds (IA-a) to (IA-e).

[0072] [ka]

[0073] [Each symbol in the formula has the same meaning as defined above.] Among these, (IA-a), (IA-b) and (IA-d) are preferred. Specific examples of suitable N-oxide aromatic heterocyclic compounds (IA) include the following compounds:

[0074] [ka]

[0075] [In the formula, R 1aa , R 1bb , R 1cc and R 1dd are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 represents an aralkyl group; n R 1ee are independently a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 represents an aralkyl group; n represents an integer of 0 to 4. R 1aa , R 1bb , R 1cc and R 1dd are preferably each independently a hydrogen atom, a cyano group or C 1-6 is an alkyl group; n R 1ee are preferably each independently 1-6 is an alkoxy-carbonyl group; n is preferably 0 or 1.

[0076] Specific examples of the N-oxide aromatic heterocyclic compound (IB) include the following N-oxide aromatic heterocyclic compounds (IB-a) to (IB-ff).

[0077] [ka]

[0078] [ka]

[0079] [Each symbol in the formula has the same meaning as defined above.] Among these, (IB-e), (IB-u) and (IB-w) are preferred. Specific preferred examples of the N-oxide aromatic heterocyclic compound (IB) include the following compounds:

[0080] [ka]

[0081] [In the formula, R 2aa , R 2bb and R 2cc are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 represents an aralkyl group; n R 2ee are independently a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 represents an aralkyl group; n represents an integer of 0 to 4. R 2aa , R 2bb and R 2cc are preferably each independently a hydrogen atom, C 1-6 Alkyl group or C 7-16 is an aralkyl group; n is preferably 0.

[0082] The N-oxide aromatic heterocyclic compound (Ia) may be a commercially available product, or may be produced by a method known per se.

[0083] Tetrafluoroethylene (CF2=CF2) can be produced by a known method. Tetrafluoroethylene is a gas at room temperature under atmospheric pressure, and is therefore added to the reaction system by inflow. At this time, tetrafluoroethylene diluted with nitrogen gas may be introduced. The amount of tetrafluoroethylene used is usually 1 to 100 moles, preferably 1 to 10 moles, per mole of the N-oxide aromatic heterocyclic compound (Ia).

[0084] The reaction is carried out using a proton source. The proton source may be present from the start of the reaction, may be added during the reaction, or may be a compound generated during the reaction (e.g., hydrogen fluoride). From the viewpoint of reaction rate, however, it is preferable that the proton source be present from the start of the reaction. Examples of proton sources include inorganic acids, organic acids, and water, and more specifically, hydrogen fluoride, hydrogen chloride, ammonium salts, water, and buffer solutions. Among these, water and hydrogen fluoride are preferred. The water may be water molecules hydrated in the raw material N-oxide aromatic heterocyclic compound (Ia). The hydrogen fluoride may be hydrogen fluoride molecules generated during the reaction process. The amount of the proton source used can be selected appropriately, but in the case of water or a buffer solution, it is preferably 0.05 to 0.5 times the volume of the solvent described below. Furthermore, when the proton source is, for example, the hydrated water molecule, it is preferably 1 to 10 moles per mole of the N-oxide aromatic heterocyclic compound (Ia). Furthermore, when the proton source is, for example, hydrogen fluoride molecules generated during the reaction, it is preferably 1 mole per mole of the N-oxide aromatic heterocyclic compound (Ia).

[0085] The reaction is carried out in the presence of a base. The inventors' research has revealed a problem in that a side reaction occurs in the following reaction in the above-mentioned reaction mechanism.

[0086] [ka]

[0087] To solve this problem, in the present invention, a base is added to the reaction system to promote proton abstraction in the intermediate, thereby increasing the reaction rate and reducing side reactions, thereby improving the yield.

[0088] In this specification, the base is a base that can abstract a proton from the intermediate, and examples of such bases include Bronsted bases. The base may be converted to a Bronsted base in the system. The bases are broadly classified into bases containing an N atom and bases not containing an N atom. Examples of the base containing an N atom include an amine compound, an ammonium compound, an imine compound, and an iminium compound.

[0089] The amine compound is, for example, a compound represented by the following formula (b1):

[0090] [ka]

[0091] [In the formula, R1, R2, and R3 each independently represent a monovalent organic group, or R1 and R2 may be joined together to form an optionally substituted nitrogen-containing heterocycle, or R1, R2, and R3 may be joined together to form a nitrogen-containing bicyclocycle.

[0092] The ammonium compound is, for example, a compound represented by the following formula (b2).

[0093] [ka]

[0094] [In the formula, R1, R2, and R3 each independently represent a monovalent organic group, or R1 and R2 may be joined together to form an optionally substituted nitrogen-containing heterocycle, or R1, R2, and R3 may be joined together to form a nitrogen-containing bicyclocycle; R4 represents a hydrogen atom or a monovalent organic group; R5 - indicates a counter anion.]

[0095] In the above formula (b1) and the above formula (b2), R1, R2 and R3 are preferably each independently selected from the group consisting of C 1-20 Alkyl group (e.g., methyl, ethyl, isopropyl, stearyl), C 1-6 Alkyl-carbonyl group (e.g., acetyl), C 6-10 an aryl group (e.g., phenyl), or an aromatic heterocyclic group (e.g., pyridyl), or R1 and R2 together form C 1-6 They form a nitrogen-containing heterocycle (e.g., piperazine) which may be substituted by an alkyl group, or R1, R2 and R3 together form a nitrogen-containing bicyclo ring (e.g., 1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane). In the above formula (b2), R4 is preferably a hydrogen atom or C 1-6 It is an alkyl group. In the above formula (b2), R5 - is preferably a halide ion (e.g., a fluoride ion (F - )) or hydroxide ion (OH - )

[0096] Specific examples of suitable amine compounds include the following compounds:

[0097] [ka]

[0098] Specific examples of suitable ammonium compounds include the following compounds:

[0099] [ka]

[0100] The imine compound is, for example, a compound represented by the following formula (b3).

[0101] [ka]

[0102] [In the formula, R6 represents a hydrogen atom or a monovalent organic group; R7 represents a divalent organic group, or R6 and R7 may be joined together to form an optionally substituted unsaturated nitrogen-containing heterocycle.

[0103] The iminium compound is, for example, a compound represented by the following formula (b4).

[0104] [ka]

[0105] [In the formula, R6 and R8 each independently represent a hydrogen atom or a monovalent organic group; R7 represents a divalent organic group, or R6 and R7 may be taken together to form an optionally substituted unsaturated nitrogen-containing heterocycle; R9 - indicates a counter anion.]

[0106] In the formula (b3) and the formula (b4), preferably, R6 is a hydrogen atom, and R7 is a C 1-6 an alkylidene group (e.g., methylidene), or R6 and R7 together form C 1-6 Alkyl group or di-C 1-6 An unsaturated nitrogen-containing heterocycle (eg, pyridine, pyrimidine, quinoline, octahydropyrimido[1,2-a]azepine) optionally substituted with an alkylamino group may be formed. In the above formula (b4), R8 is preferably a hydrogen atom. In the above formula (b4), R9 - is preferably a halide ion (e.g., a fluoride ion (F - )).

[0107] Specific examples of suitable imine compounds include the following compounds:

[0108] [ka]

[0109] Specific examples of suitable iminium compounds include the following compounds:

[0110] [ka]

[0111] Examples of bases that do not contain an N atom include metal alkoxides and inorganic bases. The metal alkoxide is, for example, R 10 OM (in the formula, R 10 is C 1-6 represents an alkyl group, and M represents an alkali metal. Specific examples include potassium tert-butoxide, sodium tert-butoxide, cesium tert-butoxide, potassium n-butoxide, sodium n-butoxide, and cesium n-butoxide. Examples of inorganic bases include halide salts such as potassium fluoride, sodium fluoride, and cesium fluoride; hydroxide salts such as calcium hydroxide, aluminum hydroxide, potassium hydroxide, and sodium hydroxide; phosphates such as sodium monohydrogen phosphate and sodium dihydrogen phosphate; carbonates such as potassium carbonate; hydrogen carbonates such as sodium hydrogen carbonate; and acetates such as sodium acetate.

[0112] The base is appropriately selected depending on the type of N-oxide aromatic heterocyclic compound (Ia). The amount of the base used will vary depending on the type of base, but is usually 1 to 10 moles, preferably 1 to 5 moles, per mole of the N-oxide aromatic heterocyclic compound (Ia).

[0113] The reaction is carried out in a solvent selected from aromatic hydrocarbon solvents, ester solvents, and ether solvents, which can dissolve tetrafluoroethylene well and produce the difluoromethyl-substituted aromatic heterocyclic compound (IIa) in good yield with few by-products. Examples of aromatic hydrocarbon solvents include toluene, xylene, and nitrobenzene. Examples of the ester solvent include butyl acetate and octyl acetate. Examples of the ether solvent include dibutyl ether and cyclopentyl methyl ether. In view of the reaction temperature, the solvent used in the reaction is preferably a solvent having a boiling point of 80° C. or higher, more preferably a solvent having a boiling point of 100° C. or higher, and particularly preferably a solvent having a boiling point of 110° C. or higher. Examples of such solvents include toluene, xylene, nitrobenzene, butyl acetate, octyl acetate, dibutyl ether, and cyclopentyl methyl ether, with toluene, xylene, and butyl acetate being preferred. The amount of the solvent used is usually 100 to 1000 times, and preferably 100 to 200 times, the volume of the N-oxide aromatic heterocyclic compound (Ia).

[0114] The reaction may be carried out in a flow system while tetrafluoroethylene is introduced into a mixture of the N-oxide aromatic heterocyclic compound (Ia), a proton source, and a solvent, or may be carried out in a closed system after tetrafluoroethylene is introduced into the mixture of the N-oxide aromatic heterocyclic compound (Ia), a proton source, and a solvent. From the viewpoints of reaction efficiency, yield, and reduction of by-products, the reaction is preferably carried out in a closed system, and is preferably carried out within a pressure range of 0.1 to 100.0 MPa, particularly preferably 0.1 to 10.0 MPa. The N-oxide aromatic heterocyclic compound (Ia) has the formula (IA) and R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, these form the above C 6-10 When an arene is formed, the reaction is preferably carried out under pressure within the range of 0.1 to 10.0 MPa, more preferably 0.1 to 1.0 MPa, and particularly preferably 0.1 to 0.5 MPa, in order to facilitate the reaction and increase the reaction rate. On the other hand, when the N-oxide aromatic heterocyclic compound (Ia) is represented by the formula (IA), and the above C 6-10 If no arene is formed, the pressure may be within the above range, but in order to shorten the reaction time, it is also preferable to carry out the reaction under a pressure within the range of 0.1 to 30.0 MPa, preferably within the range of 1.5 to 3.0 MPa, and particularly within the range of 2.0 to 2.5 MPa. It is preferable to degas the reaction system before introducing tetrafluoroethylene, and the reaction is preferably carried out under a nitrogen atmosphere.

[0115] The reaction is preferably carried out in the presence of a buffer solution of pH 5.0 to 8.0, more preferably in the presence of a buffer solution of pH 5.0 to 7.0. This reduces the production of by-products and improves the yield. An example of such a buffer solution is a phosphate buffer solution (pH 7.0 to 7.5). For example, in the case of a phosphate buffer solution (pH 7.0 to 7.5), the amount of the buffer solution used is preferably 0.05 to 0.5 times the volume of the solvent.

[0116] The reaction is usually carried out at 100°C or higher, preferably within the range of 100 to 300°C. The N-oxide aromatic heterocyclic compound (Ia) has the formula (IA) and R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, these form the above C 6-10 When an arene is formed, the reaction is preferably carried out within a range of 100 to 200°C, particularly within a range of 100 to 150°C, since the reaction proceeds easily. On the other hand, when the N-oxide aromatic heterocyclic compound (Ia) is represented by the formula (IA), and the above C 6-10 When arenes are not formed, the temperature range may be as described above, and the reaction may be carried out within a range of 200 to 300°C, particularly within a range of 200 to 250°C, since the reaction proceeds easily.

[0117] The reaction time varies depending on the type of N-oxide aromatic heterocyclic compound (Ia) and the reaction temperature, but is usually 12 to 120 hours, preferably 24 to 48 hours.

[0118] After completion of the reaction, the target difluoromethyl-substituted aromatic heterocyclic compound (IIa) can be isolated and / or purified from the reaction mixture by a conventional separation method such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc.

[0119] The vessel for reacting tetrafluoroethylene with the N-oxide aromatic heterocyclic compound (Ia) is not particularly limited as long as it does not adversely affect the reaction, and for example, a metal vessel or the like can be used. Note that, since the present invention handles olefins in a gaseous state under reaction conditions, an airtight pressure vessel is preferred. Furthermore, since compounds produced as the reaction proceeds may react with the metal of the reaction vessel and become a reaction inhibitor, a vessel lined with a resin such as PFA resin (tetrafluoroethylene-perfluoroalkoxyethylene copolymer) or glass is preferred.

[0120] The difluoromethyl-substituted aromatic heterocyclic compound (IIa) thus obtained is useful as a synthetic intermediate for pharmaceuticals or agricultural chemicals, and can lead to various pharmaceuticals or agricultural chemicals.

[0121] The manufacturing method of the present invention (invention b) will be described below. In the present invention, the aromatic heterocycle-substituted difluoroacetic acid derivative (IIIb) is produced by reacting the N-oxide aromatic heterocycle compound (Ib) with tetrafluoroethylene in the presence of compound (IIb) and a base in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent, and an ether solvent. The reaction mechanism is as follows:

[0122] [ka]

[0123] Specific examples of the N-oxide aromatic heterocyclic compound (Ib) include the following N-oxide aromatic heterocyclic compounds (IA) and (IB).

[0124] [ka]

[0125] [In the formula, X 1a is CR 1aor indicates N; X 1b is CR 1b or indicates N; X 1c is CR 1c or indicates N; X 1d is CR 1d or indicates N; R 1a , R 1b , R 1c and R 1d are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d together form a halogen atom, a cyano group, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 may form arenes; X 2a is CR2a , N, NR 2a , indicates S or O; X 2b is CR 2b or indicates N; X 2c is CR 2c , N, NR 2c , indicates S or O; R 2a , R 2b and R 2c are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 2a and R 2b , or R 2b and R 2c together form a halogen atom, a cyano group, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C optionally substituted with a substituent selected from an aralkyl group 6-10 may form an arene.] R 1a , R 1b , R 1c and R 1dare preferably each independently a hydrogen atom, a cyano group or C 1-6 alkyl group or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, C 1-6 C optionally substituted with an alkoxy-carbonyl group 6-10 An arene may be formed. R 2a , R 2b and R 2c are preferably each independently a hydrogen atom, C 1-6 Alkyl group or C 7-16 an aralkyl group, or R 2a and R 2b , or R 2b and R 2c Together, C 6-10 An arene may be formed.

[0126] In formula (IB), the bond R 2a -R 2b and bond R 2b -R 2c One of the bonds is a single bond and the other is a double bond. 2a When is S or O, bond R 2a -R 2b is a single bond, and bond R 2b -R 2c is a double bond. 2c When is S or O, bond R 2a -R 2b is a double bond, and bond R 2b -R 2c is a single bond.

[0127] Specific examples of the N-oxide aromatic heterocyclic compound (IA) include the following N-oxide aromatic heterocyclic compounds (IA-a) to (IA-e).

[0128] [ka]

[0129] [Each symbol in the formula has the same meaning as defined above.] Among these, (IA-a), (IA-b) and (IA-d) are preferred. Specific examples of suitable N-oxide aromatic heterocyclic compounds (IA) include the following compounds:

[0130] [ka]

[0131] [In the formula, R 1aa , R 1bb , R 1cc and R 1dd are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 represents an aralkyl group; n R 1ee are independently a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 represents an aralkyl group; n represents an integer of 0 to 4. R 1aa , R 1bb , R 1cc and R 1dd are preferably each independently a hydrogen atom, a cyano group or C 1-6 is an alkyl group; n R 1ee are preferably each independently 1-6 is an alkoxy-carbonyl group; n is preferably 0 or 1.

[0132] Specific examples of the N-oxide aromatic heterocyclic compound (IB) include the following N-oxide aromatic heterocyclic compounds (IB-a) to (IB-ff).

[0133] [ka]

[0134] [ka]

[0135] [Each symbol in the formula has the same meaning as defined above.] Among these, (IB-e), (IB-u) and (IB-w) are preferred. Specific preferred examples of the N-oxide aromatic heterocyclic compound (IB) include the following compounds:

[0136] [ka]

[0137] [In the formula, R 2aa , R 2bb and R 2cc are independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 represents an aralkyl group; n R 2ee are independently a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkyl sulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 represents an aralkyl group; n represents an integer of 0 to 4. R 2aa , R 2bb and R 2cc are preferably each independently a hydrogen atom, C 1-6 Alkyl group or C 7-16 is an aralkyl group; n is preferably 0.

[0138] The N-oxide aromatic heterocyclic compound (Ib) may be a commercially available product, or may be produced by a method known per se.

[0139] Tetrafluoroethylene (CF2=CF2) can be produced by a known method. Tetrafluoroethylene is a gas at room temperature under atmospheric pressure, and is therefore added to the reaction system by inflow. At this time, tetrafluoroethylene diluted with nitrogen gas may be introduced. The amount of tetrafluoroethylene used is usually 1 to 100 moles, preferably 1 to 10 moles, per mole of the N-oxide aromatic heterocyclic compound (Ib).

[0140] The reaction is carried out in the presence of compound (IIb). R in compound (IIb) is preferably a halogen atom, a cyano group, C 1-6 Alkoxy groups and C 1-6 C optionally substituted with a group selected from haloalkoxy groups 1-8 Alkyl group; halogen atom, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 C, each of which may be substituted with a group selected from haloalkoxy groups 7-16 Aralkyl group or C 6-10 An aryl group is preferred, and C is more preferred. 1-6 It is an alkyl group. Y in compound (IIb) is preferably O or NR Y and more preferably O. R in compound (IIb) Y is preferably a hydrogen atom or C 1-6 They are alkyl groups or, together with R, form a 5- or 6-membered nitrogen-containing heterocycle (eg, morpholine) with the nitrogen atom to which they are attached. Specific preferred examples of compound (IIb) include butanol, morpholine, and the like. The amount of compound (IIb) used can be appropriately selected, but is preferably 0.05 to 0.5 times the volume of the solvent described below.

[0141] The reaction is carried out in the presence of a base. The inventors' research has revealed a problem in that a side reaction occurs in the following reaction in the above-mentioned reaction mechanism.

[0142] [ka]

[0143] To solve this problem, in the present invention, a base is added to the reaction system to promote proton abstraction in the intermediate, thereby increasing the reaction rate and reducing side reactions, thereby improving the yield.

[0144] In this specification, the base is a base that can abstract a proton from the intermediate, and examples of such bases include Bronsted bases. The base may be converted to a Bronsted base in the system. The bases are broadly classified into bases containing an N atom and bases not containing an N atom. Examples of the base containing an N atom include an amine compound, an ammonium compound, an imine compound, and an iminium compound.

[0145] The amine compound is, for example, a compound represented by the following formula (b1):

[0146] [ka]

[0147] [In the formula, R1, R2, and R3 each independently represent a monovalent organic group, or R1 and R2 may be joined together to form an optionally substituted nitrogen-containing heterocycle, or R1, R2, and R3 may be joined together to form a nitrogen-containing bicyclocycle.

[0148] The ammonium compound is, for example, a compound represented by the following formula (b2).

[0149] [ka]

[0150] [In the formula, R1, R2, and R3 each independently represent a monovalent organic group, or R1 and R2 may be joined together to form an optionally substituted nitrogen-containing heterocycle, or R1, R2, and R3 may be joined together to form a nitrogen-containing bicyclocycle; R4 represents a hydrogen atom or a monovalent organic group; R5 - indicates a counter anion.]

[0151] In the above formula (b1) and the above formula (b2), R1, R2 and R3 are preferably each independently selected from the group consisting of C 1-20 Alkyl group (e.g., methyl, ethyl, isopropyl, stearyl), C 1-6 Alkyl-carbonyl group (e.g., acetyl), C 6-10 an aryl group (e.g., phenyl), or an aromatic heterocyclic group (e.g., pyridyl), or R1 and R2 together form C 1-6 They form a nitrogen-containing heterocycle (e.g., piperazine) which may be substituted by an alkyl group, or R1, R2 and R3 together form a nitrogen-containing bicyclo ring (e.g., 1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane). In the above formula (b2), R4 is preferably a hydrogen atom or C 1-6 It is an alkyl group. In the above formula (b2), R5 - is preferably a halide ion (e.g., a fluoride ion (F - )) or hydroxide ion (OH - )

[0152] Specific examples of suitable amine compounds include the following compounds:

[0153] [ka]

[0154] Specific examples of suitable ammonium compounds include the following compounds:

[0155] [ka]

[0156] The imine compound is, for example, a compound represented by the following formula (b3).

[0157] [ka]

[0158] [In the formula, R6 represents a hydrogen atom or a monovalent organic group; R7 represents a divalent organic group, or R6 and R7 may be joined together to form an optionally substituted unsaturated nitrogen-containing heterocycle.

[0159] The iminium compound is, for example, a compound represented by the following formula (b4).

[0160] [ka]

[0161] [In the formula, R6 and R8 each independently represent a hydrogen atom or a monovalent organic group; R7 represents a divalent organic group, or R6 and R7 may be taken together to form an optionally substituted unsaturated nitrogen-containing heterocycle; R9 - indicates a counter anion.]

[0162] In the formula (b3) and the formula (b4), preferably, R6 is a hydrogen atom, and R7 is a C 1-6an alkylidene group (e.g., methylidene), or R6 and R7 together form C 1-6 Alkyl group or di-C 1-6 An unsaturated nitrogen-containing heterocycle (eg, pyridine, pyrimidine, quinoline, octahydropyrimido[1,2-a]azepine) optionally substituted with an alkylamino group may be formed. In the above formula (b4), R8 is preferably a hydrogen atom. In the above formula (b4), R9 - is preferably a halide ion (e.g., a fluoride ion (F - )).

[0163] Specific examples of suitable imine compounds include the following compounds:

[0164] [ka]

[0165] Specific examples of suitable iminium compounds include the following compounds:

[0166] [ka]

[0167] Examples of bases that do not contain an N atom include metal alkoxides and inorganic bases. The metal alkoxide is, for example, R 10 OM (in the formula, R 10 is C 1-6 represents an alkyl group, and M represents an alkali metal. Specific examples include potassium tert-butoxide, sodium tert-butoxide, cesium tert-butoxide, potassium n-butoxide, sodium n-butoxide, and cesium n-butoxide. Examples of inorganic bases include halide salts such as potassium fluoride, sodium fluoride, and cesium fluoride; hydroxide salts such as calcium hydroxide, aluminum hydroxide, potassium hydroxide, and sodium hydroxide; phosphates such as sodium monohydrogen phosphate and sodium dihydrogen phosphate; carbonates such as potassium carbonate; hydrogen carbonates such as sodium hydrogen carbonate; and acetates such as sodium acetate.

[0168] The base is appropriately selected depending on the type of N-oxide aromatic heterocyclic compound (Ib). The amount of the base used will vary depending on the type of base, but is usually 1 to 10 moles, preferably 1 to 5 moles, per mole of the N-oxide aromatic heterocyclic compound (Ib).

[0169] The reaction is carried out in a solvent selected from aromatic hydrocarbon solvents, ester solvents, and ether solvents, which can dissolve tetrafluoroethylene well and produce the aromatic heterocycle-substituted difluoroacetic acid derivative (IIIb) with few by-products. Examples of aromatic hydrocarbon solvents include toluene, xylene, and nitrobenzene. Examples of the ester solvent include butyl acetate and octyl acetate. Examples of the ether solvent include dibutyl ether and cyclopentyl methyl ether. In view of the reaction temperature, the solvent used in the reaction is preferably a solvent having a boiling point of 80° C. or higher, more preferably a solvent having a boiling point of 100° C. or higher, and particularly preferably a solvent having a boiling point of 110° C. or higher. Examples of such solvents include toluene, xylene, nitrobenzene, butyl acetate, octyl acetate, dibutyl ether, and cyclopentyl methyl ether, with toluene and butyl acetate being preferred. The amount of the solvent used is usually 100 to 1000 times, and preferably 100 to 200 times, the volume of the N-oxide aromatic heterocyclic compound (Ib).

[0170] The reaction may be carried out in a flow system while tetrafluoroethylene is introduced into a mixture of N-oxide aromatic heterocyclic compound (Ib), compound (IIb), and a solvent, or may be carried out in a closed system after tetrafluoroethylene is introduced into a mixture of N-oxide aromatic heterocyclic compound (Ib), compound (IIb), and a solvent. From the viewpoints of reaction efficiency and reduction of by-products, the reaction is preferably carried out in a closed system, and is preferably carried out within a pressure range of 0.1 to 100.0 MPa, particularly preferably 0.1 to 10.0 MPa. N-oxide aromatic heterocyclic compound (Ib) is of formula (IA) and R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, these form the above C 6-10 When an arene is formed, the reaction is preferably carried out under pressure within the range of 0.1 to 10.0 MPa, more preferably 0.1 to 1.0 MPa, and particularly preferably 0.1 to 0.5 MPa, in order to facilitate the reaction and increase the reaction rate. On the other hand, when the N-oxide aromatic heterocyclic compound (Ib) is represented by the formula (IA) and the above C 6-10 If no arene is formed, the pressure may be within the above range, but it is preferable to carry out the reaction under pressure within the range of 0.1 to 30.0 MPa, preferably 1.5 to 3.0 MPa, and particularly preferably 2.0 to 2.5 MPa, since the reaction proceeds easily and the reaction rate increases. It is preferable to degas the reaction system before introducing tetrafluoroethylene, and the reaction is preferably carried out under a nitrogen atmosphere.

[0171] The reaction is usually carried out at 100°C or higher, preferably within the range of 100 to 300°C. N-oxide aromatic heterocyclic compound (Ib) is of formula (IA) and R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, these form the above C 6-10When an arene is formed, the reaction is preferably carried out within a range of 100 to 200°C, particularly within a range of 100 to 150°C, since this facilitates the reaction and increases the reaction rate. On the other hand, when the N-oxide aromatic heterocyclic compound (Ib) is represented by the formula (IA) and the above C 6-10 If arene is not formed, the temperature range may be within the above range, but it is preferable to carry out the reaction within the range of 200 to 300°C, particularly within the range of 200 to 250°C, since this facilitates the reaction and increases the reaction rate. The reaction time varies depending on the types of N-oxide aromatic heterocyclic compound (Ib) and compound (IIb) and the reaction temperature, but is usually 12 to 120 hours, preferably 24 to 48 hours.

[0172] After completion of the reaction, the desired aromatic heterocycle-substituted difluoroacetic acid derivative (IIIb) can be isolated and / or purified from the reaction mixture by a conventional separation method such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, or chromatography.

[0173] The vessel for reacting tetrafluoroethylene with the N-oxide aromatic heterocyclic compound (Ib) is not particularly limited as long as it does not adversely affect the reaction, and for example, a metal vessel or the like can be used. Note that, since the present invention handles olefins in a gaseous state under the reaction conditions, an airtight pressure-resistant vessel is preferred. Furthermore, since compounds produced as the reaction proceeds may react with the metal of the reaction vessel and become a reaction inhibitor, a vessel lined with a resin such as PFA resin (tetrafluoroethylene-perfluoroalkoxyethylene copolymer) or glass is preferred.

[0174] The aromatic heterocycle-substituted difluoroacetic acid derivative (IIIb) thus obtained is useful as a synthetic intermediate for pharmaceuticals or agricultural chemicals, and can be obtained by a known method, for example, in the case of the aromatic heterocycle-substituted difluoroacetic acid derivative (IIIb) where Y is O, by hydrolysis followed by a decarboxylation step, to obtain a compound of formula (IVb):

[0175] [ka]

[0176] This can lead to a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by the following formula: [Example]

[0177] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. [Analysis method] Nuclear magnetic resonance spectroscopy (NMR) was measured using a JNM-AL300 manufactured by JEOL Ltd. 1 H-NMR was measured at 300 MHz using tetramethylsilane as the reference. Mass spectrometry (LC-MS) was performed using an Agilent Technologies liquid chromatograph mass spectrometry system (LCMS6120B). Mass spectrometry (GC-MS) was performed using a Shimadzu Corporation gas chromatograph mass spectrometer (GCMS-QP5000V2 or GCMS-QP2010Ultra) by electron ionization (EI). Quantitative analysis of yield (GC) was performed using an Agilent Technologies gas chromatograph system (Agilent6850) with a DB-1 column, 60 m, 0.25 mm diameter, and 1 μm film thickness.

[0178] [Example 1]

[0179] [ka]

[0180] A catalyst screening vessel (HIP-7506 model) manufactured by SynFlex was used as the reaction vessel. Xylene (10 ml) and water (1 ml) were added, stirred, and maintained at 25°C. Quinoline N-oxide (109 mg, 0.751 mmol, Compound 1) and various bases (0.751 mmol) were then added, and the mixture was degassed under vacuum. Tetrafluoroethylene diluted to 50% with nitrogen gas was added until the reactor pressure reached 0.2 MPa, and the mixture was heated and stirred at 140°C for 120 hours. NMR, GC, and GC-MS analyses of the crude liquid after the reaction were performed, and the yield of Compound 2 was calculated. Compound 2 1 The H-NMR and GC-MS results are shown below. 1 H-NMR(CDCl3)δ 8.34 (d, 1H), 8.15 (d, 1H), 7.90 (d, 1H), 7.80 (dd, 1H), 7.74 (d, 1H), 7.65 (dd, 1H), 6.79 (t, 1H) GC-MS(EI):[M+]=179 Table 1 below shows the yield (%) of Compound 2 for each base, along with the results of a control experiment in which no base was added for comparison.

[0181] [Table 1]

[0182] [Example 2]

[0183] [ka]

[0184] A crude liquid containing Compound 3 was obtained from Compound 1 in the same manner as in Example 1, except that xylene and water were replaced with butyl acetate and butanol. After completion of the reaction, the crude liquid was subjected to NMR, GC, and GC-MS analysis to calculate the yield of Compound 3. Compound 3 1 H-NMR and LC-MS are shown below. 1H-NMR(CDCl3)δ 8.35 (d, 1H), 8.15 (d, 1H), 7.89 (d, 1H), 7.72-7.81(m, 2H), 7.63 (t, 1H), 4.36 (t, 2H), 1.67 (tt, 2H), 1.35 (tt, 2H), 0.88 (t, 3H) LC-MS: [M+1]=280 Table 2 below shows the yield (%) of compound 3 for each base, along with the results of a control experiment in which no base was added for comparison.

[0185] [Table 2] [Industrial Applicability]

[0186] According to the present invention (Invention a), a difluoromethyl-substituted aromatic heterocyclic compound (IIa) can be produced in a single step with a small amount of by-products and in a good yield by a simple and inexpensive method in which tetrafluoroethylene is introduced into an N-oxide aromatic heterocyclic compound (Ia) in a specific solvent in the presence of a base.

[0187] According to the present invention (Invention b), an aromatic heterocycle-substituted difluoroacetic acid derivative (IIIb) can be produced in a single step in a good yield with few by-products by a simple and inexpensive method in which tetrafluoroethylene is introduced into an N-oxide aromatic heterocyclic compound (Ib) in the presence of compound (IIb) and a base in a specific solvent.

[0188] This application is based on Patent Application No. 2021-131010 filed in Japan on August 11, 2021, the contents of which are incorporated in full herein.

Claims

1. In a solvent selected from an aromatic hydrocarbon solvent, an ester solvent, and an ether solvent, in the presence of a base, a compound of formula (Ia): 【Chemistry 1】 The compound represented by formula (IIa): 【Chemistry 2】 A method for producing a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by The reaction is carried out in the range of 100 to 300°C, and The solvent has a boiling point of 100°C or higher. Manufacturing method.

2. The method according to claim 1, wherein the reaction is carried out in the range of 0.1 to 10.0 MPa.

3. The method according to claim 1, wherein the reaction is carried out in the presence of a pH 5.0 to 8.0 buffer solution.

4. The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (Ia) is represented by formula (IA) or (IB): 【Transformation 3】 [In the formula, X １ａ is CR １ａ or indicates N; X １ｂ is CR １ｂ or indicates N; X １ｃ is CR １ｃ or indicates N; X １ｄ is CR １ｄ or indicates N; R １ａ , R １ｂ , R １ｃ and R １ｄ are independently a hydrogen atom, a halogen atom, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkyl sulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl group or C ７－１６ represents an aralkyl group, or R １ａ and R １ｂ , R １ｂ and R １ｃ , or R １ｃ and R １ｄ together form a halogen atom, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkyl sulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl groups and C ７－１６ C optionally substituted with a substituent selected from an aralkyl group ６－１０ may form an arene; X ２ａ is CR ２ａ , N, N.R. ２ａ , represents S or O; X ２ｂ is CR ２ｂ or indicates N; X ２ｃ is CR ２ｃ , N, N.R. ２ｃ , represents S or O; R ２ａ , R ２ｂ and R ２ｃ are independently a hydrogen atom, a halogen atom, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkyl sulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl group or C ７－１６ represents an aralkyl group, or R ２ａ and R ２ｂ , or R ２ｂ and R ２ｃ together form a halogen atom, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkyl sulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl groups and C ７－１６ C optionally substituted with a substituent selected from an aralkyl group ６－１０ An arene may be formed.] 2. The method according to claim 1, wherein the compound is an N-oxide aromatic heterocyclic compound represented by the formula:

5. in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent, and an ether solvent, [In the formula, R is C １－８ Alkyl group, C ３－８ Cycloalkyl group, C ７－１６ Aralkyl group or C ６－１０ represents an aryl group, wherein the C １－８ The alkyl group may be a halogen atom, a cyano group, or a C １－６ Alkoxy groups and C １－６ haloalkoxy groups, ３－８ Cycloalkyl group, C ７－１６ Aralkyl groups and C ６－１０ The aryl group may be a halogen atom, a cyano group, １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy groups and C １－６ haloalkoxy groups, Y is O, S or NR Ｙ indicates, R Ｙ is a hydrogen atom or C １－８ It may represent an alkyl group, or may be taken together with R to form a nitrogen-containing heterocycle together with the nitrogen atom to which it is attached. and a base, 【Chemistry 4】 and reacting an N-oxide aromatic heterocyclic compound having a partial structure represented by formula (IIIb): with tetrafluoroethylene. 【Transformation 5】 [Each symbol in the formula has the same meaning as defined above.] A method for producing an aromatic heterocycle-substituted difluoroacetic acid derivative having a partial structure represented by The reaction is carried out in the range of 100 to 300°C, and The solvent has a boiling point of 100°C or higher. Manufacturing method.

6. The method according to claim 5, wherein the reaction is carried out in the range of 0.1 to 10.0 MPa.

7. The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (Ib) is a compound represented by formula (IA) or (IB): 【Transformation 6】 [In the formula, X １ａ is CR １ａ or indicates N; X １ｂ is CR １ｂ or indicates N; X １ｃ is CR １ｃ or indicates N; X １ｄ is CR １ｄ or indicates N; R １ａ , R １ｂ , R １ｃ and R １ｄ are independently a hydrogen atom, a halogen atom, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkyl sulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl group or C ７－１６ represents an aralkyl group, or R １ａ and R １ｂ , R １ｂ and R １ｃ , or R １ｃ and R １ｄ together form a halogen atom, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkyl sulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl groups and C ７－１６ C optionally substituted with a substituent selected from an aralkyl group ６－１０ may form an arene; X ２ａ is CR ２ａ , N, N.R. ２ａ , represents S or O; X ２ｂ is CR ２ｂ or indicates N; X ２ｃ is CR ２ｃ , N, N.R. ２ｃ , represents S or O; R ２ａ , R ２ｂ and R ２ｃ are independently a hydrogen atom, a halogen atom, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkyl sulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl group or C ７－１６ represents an aralkyl group, or R ２ａ and R ２ｂ , or R ２ｂ and R ２ｃ together form a halogen atom, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkyl sulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl groups and C ７－１６ C optionally substituted with a substituent selected from an aralkyl group ６－１０ An arene may be formed.] The method according to claim 5, wherein the compound is an N-oxide aromatic heterocyclic compound represented by the formula:

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